The isolation and structure elucidation of zaragozic acid C, a novel potent squalene synthase inhibitor.

Dufresne, Claude; Wilson, Kenneth E.; Zink, Deborah L.; Smith, Jack L.; Bergstrom, James D.; Kurtz, Marc M.; Rew, Deborah J.; Nallin, Mary; Jenkins, Rosalind G.; Bartizal, Ken; Trainor, C.; Bills, Gerald F.; Meinz, María; Huang, Leeyuan; Onishi, Janet C.; Milligan, James A.; Mojena, Marina; Peláez, Fernando

doi:10.1016/s0040-4020(01)88327-7

Cited by 58 publications

(31 citation statements)

References 8 publications

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“…More recently, a remarkable photochemical C–H acylation was utilized to cyclize a complicated ring system ( Scheme 22 ). Inoue et al presented a total synthesis of zaragozic acid C ( 145 ) [ 84 ], a potent inhibitor of mammalian squalene synthase [ 85 ]. Natural acid 145 is characterized by a dioxabicyclo[3.2.1]octane architecture with an array of six stereocenters.…”

Section: Radical Cyclizationsmentioning

confidence: 99%

Recent Advances in Substrate-Controlled Asymmetric Cyclization for Natural Product Synthesis

Kim

Han

et al. 2017

Molecules

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Asymmetric synthesis of naturally occurring diverse ring systems is an ongoing and challenging research topic. A large variety of remarkable reactions utilizing chiral substrates, auxiliaries, reagents, and catalysts have been intensively investigated. This review specifically describes recent advances in successful asymmetric cyclization reactions to generate cyclic architectures of various natural products in a substrate-controlled manner.

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Section: Radical Cyclizationsmentioning

confidence: 99%

Recent Advances in Substrate-Controlled Asymmetric Cyclization for Natural Product Synthesis

Kim

Han

et al. 2017

Molecules

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“…The zaragozic acids [6][7][8][9][10][11] and squalestatins, [12][13][14][15] fungal metabolites isolated and characterized independently by researchers at Merck, Glaxo, and Tokyo Noko University/Mitsubishi Kasei Corporation in 1992, have been shown to be picomolar competitive inhibitors of the enzyme squalene synthase (Fig. 1).…”

Section: Zaragozic Acidsmentioning

confidence: 99%

Total Synthesis of the Squalene Synthase Inhibitor Zaragozic Acid C

Nakamura

2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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Zaragozic acids and squalestatins were documented by Merck, Glaxo, and Tokyo Noko University/Mitsubishi Kasei Corporation as part of a program aimed at identifying novel inhibitors of squalene synthase, as well as farnesyl transferase. These natural products have attracted considerable attention from numerous synthetic chemists because of their therapeutic potential and novel architecture. This review highlights our total syntheses of zaragozic acid C by two convergent strategies. The key steps in our first-generation synthesis involve 1) simultaneous creation of the C4 and C5 quaternary stereocenters through the Sn(OTf) 2 -promoted aldol coupling reaction between the a a-keto ester and silyl ketene thioacetal derived from L-and D-tartaric acids, respectively; and 2) construction of the bicyclic core structure via acid-catalyzed internal ketalization under kinetically controlled conditions. The second-generation strategy relies on a tandem carbonyl ylide formation/1,3-dipolar cycloaddition approach and features elongation of the C1 alkyl side chain through an olefin cross-metathesis as well as high convergency and flexibility.

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“…This enzyme, responsible for the reductive dimerization of two farnesyl pyrophosphate molecules with the formation of squalene, is now very extensively studied. Inhibitors of squalene synthetase were found among the secondary metabolites produced by some of the simplest fungi [76][77][78][79][80][81][82][83][84]. These compounds have an unusual structure of the nucleus, representing a 4,6,7-trihydroxy-2,8-dioxabicyclo[3, 2.1]octane-3,4,5-tricarboxylic acid, and different 6-O-acyl and 1-alkyl substituents.…”

Section: Antibiotics Inhibiting the Late Stages Of Cholesterol Biosynmentioning

confidence: 99%

“…The new inhibitors, referred to as saragosic acids [76] and squalestatins [77,78], even in picomole concentrations are efficient as competitive inhibitors of sqdalene synth~tase with respect to its substrate (famesyl pyrophosphate). They inhibit both the transformation of famesyl pyrophosphate into presqualene pyrophosphate and the conversion of the latter compound into squalene [81,82].…”

Section: Antibiotics Inhibiting the Late Stages Of Cholesterol Biosynmentioning

confidence: 99%

Antibiotics inhibiting the biosynthesis of cholesterol (a review)

Тренин

Катруха

1997

Pharm Chem J

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The several decades that have passed since the introduction of penicillin into medical practice is essentially the age of antibiotics. Their wide application was very fruitful and allowed the solution of a number of fundamental problems both in the field of infection pathology and in treating diseases of a non-infection nature [ 1,2]. As is well known, antibiotics are not only successfully used as antimicrobial preparations, but are also applied in oncology as antitumor drugs. Moreover, it was the discovery of microbial metabolites-immunomodulators and the creation of immunodepressants such as eyclosporin A and FK 506 that made possible surgical operations involving the transplantation of organs and tissues [3 -5].

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The isolation and structure elucidation of zaragozic acid C, a novel potent squalene synthase inhibitor.

Cited by 58 publications

References 8 publications

Recent Advances in Substrate-Controlled Asymmetric Cyclization for Natural Product Synthesis

Recent Advances in Substrate-Controlled Asymmetric Cyclization for Natural Product Synthesis

Total Synthesis of the Squalene Synthase Inhibitor Zaragozic Acid C

Antibiotics inhibiting the biosynthesis of cholesterol (a review)

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